The genomic size of Human Immunodeficiency Virus (HIV-1) is approximately 9.7 kB with open reading frames encoding several viral proteins. Gene products (structural, regulatory and accessory viral proteins) arise from spliced and unspliced mRNAs and can affect viral replication in various cell types. Since heterogeneity among HIV-1 retroviral genomes is a distinct feature of Lentiviruses, molecular clones could provide useful reagents for studying their biochemical and physical properties. HIV-1 isolates can be divided into two major subgroups on the basis of their cellular host range in vitro: macrophage (MT) and T-cell line tropic. MT-tropic isolates infect both macrophages and peripheral blood mononuclear cells (PBMC) but are unable to replicate in transformed CD4+ T-cell lines. T-cell line tropic isolates infect both PBMC and CD4+ T-cell lines but replicate poorly or not at all primary macrophages MDM). Although T-cells are the major target for HIV-1 replication in peripheral blood, macrophages represent the predominant HIV-1 infected cell type in most tissues. Macrophages are probably the primary reservoir of HIV-1 and may be important for sustaining a persistent infection in individuals for many years. Most HIV-1 isolates we have cloned are T-cell tropic. We have succeeded in obtaining a complete molecular clone from a macrophage-tropic viral isolate. Preliminary biochemical and physical analyses have shown that the spontaneous shedding of the envelope protein(gp120) is drastically different from the typical T-cell line variants. Also the effects of several accessory genes (non-essential in in vitro infections) appear to be dispensable. Mutations in VPU, VPR, or NEF modestly reduced viral replication of the AD8-2 clone in either PBMC or macrophages.